UNDERSTANDING THE ROLE OF TM2D FAMILY GENES IN NOTCH SIGNALING AND ALZHEIMER'S DISEASE

项目总结/摘要 阿尔茨海默病（AD）是一种多因素的复杂神经退行性疾病， 许多遗传、表观遗传和环境因素。基因组学的进步已经发现了新的 与AD相关的基因和罕见变异。然而，这些分子机制如何 导致AD发病机制的因素在很大程度上是不确定的。与CHARGE合作 （基因组流行病学心脏和衰老研究队列）联盟，我们最近发现了一个 TM 2D 3中一种罕见的错义变异，与迟发性 AD（LOAD）.此外，一个独立小组最近的一项研究报告说，另一种罕见的误解， 在早发性AD患者中发现了变异。虽然这个基因的功能还没有被证实， 在脊椎动物体内的探索，我们的实验使用果蝇，果蝇，表明， 这种基因是一种加工APP关键酶的潜在调节因子，APP是一种前体蛋白， 产生导致AD的神经毒性Ab 42肽。在这个建议中，我们阐明了分子 TM 2D 3及其相关家族成员（TM 2D 1/2）的功能，以了解它们在APP中的作用 加工和AD发病机制。苍蝇是遗传学研究的极好模式生物 剖析神经退化的分子机制。此外，由于APP是由相同的 一组激活Notch的酶，一种在TM 2D 3突变果蝇中受影响的途径，丰富的研究 果蝇Notch信号研究的基础设施极大地促进了这种机制的研究。 体内蛋白质通过结合遗传学、细胞生物学、生物化学、电生理学和行为学 方法，我们将揭示如何TM 2D 3及其亲属调节膜蛋白水解 蛋白质，以了解该基因中罕见的错义变体如何影响LOAD和EOAD的风险， 人类这种理解将为AD发病机制提供新的见解，并将提供新的 了解AD遗传风险因素如何影响共同分子途径的框架 以促进疾病表达和进展。

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a multifactorial and complex neurodegenerative disorder that involves numerous genetic, epigenetic and environmental factors. Advances in genomics have identified new genes and rare variants that are associated with AD. However, the molecular mechanisms of how these factors contribute to AD pathogenesis are largely undefined. In collaboration with the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium, we recently identified a rare missense variant in TM2D3 that is associated with a significant increase in the risk of late-onset AD (LOAD). Furthermore, a recent study by an independent group reported that another rare missense variant was found in a patient with early-onset AD. Although the function of this gene has not been explored in vertebrates in vivo, our experiments using fruit flies, Drosophila melanogaster, suggests that this gene is a potential regulator of a key enzyme that process APP, a precursor protein that produces neurotoxic Ab42 peptides that contribute to AD. In this proposal, we elucidate the molecular function of TM2D3 and its related family members (TM2D1/2) to understand their role in APP processing and AD pathogenesis using Drosophila. Flies are excellent model organisms to genetically dissect molecular mechanisms of neurodegeneration. Moreover, since APP is processed by the same set of enzymes that activate Notch, a pathway affected in TM2D3 mutant flies, rich research infrastructure for Notch signaling studies in Drosophila greatly facilitates the mechanistic study of this protein in vivo. By combining genetic, cell biological, biochemical, electrophysiological and behavioral methodologies, we will uncover how TM2D3 and its relatives modulate proteolysis of membrane proteins to understand how rare missense variants in this gene affects the risk of LOAD and EOAD in humans. Such understanding will provide novel insights into AD pathogenesis and will deliver a new framework to understand how genetic risk factors of AD may impinge on a common molecular pathway to facilitate disease expression and progression.